The need for new antidepressant agents arises from the limited efficacy, slowness of action, and adverse side-effects of many currently available compounds. For instance, some tricyclic antidepressants can cause sedation and atropine-like effects. Still other antidepressants can produce agitation that some persons feel lead them to increase suicidal ideation.
L-phenylalanine is an essential amino acid which is decarboxylated in the brain and peripheral tissues to form 2-phenylethylamine ("PEA"). PEA is then metabolized by monoamine oxidase type B [Yang and Neff, J. Pharmacol. Exp. Ther., 187:365-371 (1973)] to form phenylacetic acid ("PAA"). PEA is normally found stored and metabolized in brain and peripheral tissues. [Sabelli et al., Acta Physiological Polonica, 24:33-40 (1973); Inwang et al., J. Neurochem., 20:1469-1473 (1973); Mosnain et al., Biol. Psychiatry, 6:235-257 (1973a); Boulton et al., Br. J. Pharmacol., 59:209-214 (1977); Jackson and Temple, Comp. Gen. Pharmacol., 1:155- 157 (1970); Phillips et al., J. Neurochem., 33:159-161 (1979); Durden and Phillips, J. Neurochem., 34:1725-1732 (1980)].
It has been reported in the art that depression is not associated with a general PEA deficit in the body. [DeLisi et al., Psychiatry Research, 13:193-201 (1984); Karoum et al., Biological Psychiatry, 19:165-178 (1984)]. Further, certain clinical observations have led some investigators to conclude that there is no association between PEA and behavioral activation, and that the antidepressant effects of monoamine oxidase inhibitors are not likely to be mediated by increased PEA or associated changes in PEA. [Murphy et al., Neurobiology of the Trace Amines, pp. 449-514 (1984)].
Contrary reports concerning PEA have appeared, however, in the psychiatric literature. Fischer and others have reported that a deficit in PEA in the body may be the cause of a form of depressive illness. [Fischer et al., Acta Physiol. Lat. Am., 17:15-21 (1967); Sabelli and Giardina, Chemical Modulation of Brain Function, Raven Press, New York, pp. 225-259 (1973); Sabelli and Mosnaim, Am. J. Psych., 131:695-699 (1974); Sabelli et al., Science, 220:1187-1188 (1983)]. It is also believed that PEA excess may contribute to some form of mania [Fischer et al., Biol. Psychiatry, 5:139-147 (1972)] and schizoaffective psychosis [Sabelli et al., J. Neuropsychiatry, 1:37-39 (1989)], and that PEA is an amphetamine-like substance which produces behavioral stimulation when administered to animals. [Nakajima et al., J. Pharmacol. Exp. Ther., 143:319-325 (1964); Fischer et al., Acta Physiol. Lat. Am., 17:15-21 (1967); Jackson, J. Pharm. Pharmacol., 24:383- 389 (1972); Sabelli and Giardina, Chemical Modulation of Brain Function, New York, Raven Press, pp. 225-59 (1973); Greenshaw, "B-phenylethylamine: A functional role at the behavioral level," Neurobiology of the Trace Amines, New Jersey, Humana Press (1984); Sabelli et al., Biol. Psychiatry, 3:273-280 (1971)]. This amphetamine-like effect, however, is weak because the PEA is rapidly destroyed by monoamine oxidase.
Karoum and coworkers [Biol. Psychiatry, 19:165-178 (1984)] reported the administration of PEA in 4 depressed patients in amounts varying from 200-1600 mg. In each case, though, the administered PEA was quantitatively metabolized to PAA. There were no noticeable pharmacological effects. PEA has also been administered to three patients in combination with phenelzine. [Carlson-Sabelli et al., "Phenylalanine Metabolism in Affective and Other Psychotic Disorders," Presentation at VII World Congress of Psychiatry, Athens, Greece (September 1989); Sabelli et al., FASEB, 3(4):A1186 (1989)]. This combination ameliorated depression in two patients. This combination is disadvantageous, however, since phenelzine does not selectively inhibit monoamine oxidase B and requires that the patient have a restricted diet.
L-Deprenyl (also known as selegiline) has previously been used as a treatment for Parkinson's disease. Symptoms of depression have also been relieved by treatment with (-) deprenyl at doses of 30 to 60 mg/day that inhibit both the A and B forms of monoamine oxidase. [Varga et al., Acta. Med. Acad. Sci. Hung., 23:289-295 (1967); Mann et al., Life Sci., 26:877-882 (1980); J. Clin. Psychopharm., 2:54-57 (1982)]. When deprenyl is administered at lower doses (5 to 10 mg/day) which selectively inhibit type B monoamine oxidase, no antidepressant effect has been observed. [Mendis et al., Psychopharmacology, 73:87-90 (1981)]. However, relief from depression can be obtained when low doses of deprenyl are combined with 250 mg of L-phenylalanine. [Birkmayer et al., J. Neural Transmission, 59:81-87 (1984); Knoll et al., U.S. Pat. No. 4,880,883]. Using higher doses of L-phenylalanine (1 to 6 grams/day), it was found that the deprenyl-phenylalanine combination produced recovery from depression in patients resistant to other treatments. [Sabelli, Proc. of the Amer. psychiat. Assoc., New Research Program and Abstracts, New York, N.Y. May 12-17, 1990:146; Sabelli, J. Clin. Psych., 52(3):137 (1991); Sabelli, "Clinical antidepressant effects of selegiline and L-phenylalanine support mood-regulating role for brain 2-phenylethylamine," FASEB, 1991].